Transforming growth factor-.beta.(TGF-.beta.) is a family of structurally related molecules denoted TGF-.beta.1, -.beta.2, -.beta.3, -.beta.4 and .beta.5; these molecules are in turn more distantly related to several other factors including inhibins/activins, Mullerian inhibitory substance, bone morphogenic proteins, the product of the decapentaplegic complex of Drosophila and Vgl of Xenopus. See Roberts, et al. Handbook of Experimental Pharmacology, Volume 95, (in press, 1990). TGF-.beta. was originally identified because of its ability to stimulate anchorage independent growth of NRK cells in synergy with TGF-.alpha., Roberts, et al., Fed. Proc. 42: 2621-2626(1983). It has subsequently been found to stimulate or to inhibit growth and differentiation of many different cell types. See Roberts, et al., 1990, supra.
TGF-.beta.s bind to at least three different receptor-like molecules; two smaller species of 53 and 73 kDa, denoted type I and type II receptors, respectively, and one larger proteoglycan-like structure denoted type III receptor or beta-glycan (Cheifetz, et al., Cell 40: 409-415 (1987); Cheifetz, et al., J. Biol. Chem. 264: 2272-2278 (1988); Andres, et al., J. Cell. Biol. 109: 3137-3146 (1989); Segarini, et al., J. Biol. Chem. 263: 8366-8370 (1988)). The biological effects of TGF-.beta. seems to be mediated by the type I receptor (Boyd and Massague, J. Biol. Chem. 264: 2272-2278 (1989)).
TGF-.beta.s are 25 kDa disulfide-bonded dimeric molecules which are synthesized and secreted as inactive high M.sub.r complexes (Pircher, et al., Cancer Res. 44: 5538-5543 (1984); Pircher, et al., Biochem. Biophys. Res. Commun. 136: 30-37 (1984); Wakefield, et al., J. Cell Biol. 105: 965-975 (1987)). The large latent complex of TGF-.beta.1 from human platelets has been purified and characterized as described by Miyazono, et al., J. Biol. Chem. 263: 6407-6415 (1988), the disclosure of which is incorporated by reference. In this complex the TGF-.beta.1 molecule is noncovalently associated with a disulphide-bonded complex of a dimer of the N-terminal propeptide of the TGF-.beta.1 precursor and a third component denoted the TGF-.beta.1 binding protein (TGF-.beta.1-BP). The platelet-derived TGF-.beta.1-BP was found to occur as several species of sizes between 125 and 160 kDa. See Miyazono, et al., supra.
The fact that TGF-.beta.s have dramatic effects on growth and differentiation of most cell types, together with the observation that they are synthesized by many different cell types, indicate that the activation of TGF-.beta.s from their high M.sub.r latent complexes must be an important regulatory step in vivo. In vitro, activation is achieved e.g. by acidification to pH values below 4, as described by Pircher, et al., and Miyazono, et al., supra. In vivo such low pH values are rarely found extracellularly. The in vivo mechanism of activation is not fully understood; possible mechanisms include proteolysis or perturbation of the carbohydrate structures of the TGF-.beta.1 propeptide in the latent complex. See Miyazono and Heldin, Nature 338: 158-160 (1989), the disclosure of which is incorporated by reference, and Lyons, et al., J. Cell Biol. 106: 1659-1665 (1988).